AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells

Abstract

Background Aryl hydrocarbon receptor (AHR)-deficient mice do not support the expansion of dendritic epidermal T cells (DETC), a resident immune cell population in the murine epidermis, which immigrates from the fetal thymus to the skin around birth. Material and Methods In order to identify the gene expression changes underlying the DETC disappearance in AHR-deficient mice, we analyzed microarray RNA-profiles of DETC, sorted from the skin of two-week-old AHR-deficient mice and their heterozygous littermates. In vitro studies were done for verification, and IL-10, AHR repressor (AHRR), and c-Kit deficient mice analyzed for DETC frequency. Results We identified 434 annotated differentially expressed genes. Gene set enrichment analysis demonstrated that the expression of genes related to proliferation, ion homeostasis and morphology differed between the two mouse genotypes. Importantly, with 1767 pathways the cluster-group “inflammation” contained the majority of AHR-dependently regulated pathways. The most abundant cluster of differentially expressed genes was “inflammation.” DETC of AHR-deficient mice were inflammatory active and had altered calcium and F-actin levels. Extending the study to the AHRR, an enigmatic modulator of AHR-activity, we found approximately 50% less DETC in AHRR-deficient mice than in wild-type-littermates. Conclusion AHR-signaling in DETC dampens their inflammatory default potential and supports their homeostasis in the skin.

Skin Resident γδ T Cell Function and Regulation in Wound Repair

“…AHR signaling has important roles in the health and disease of the immune system and is generally involved in cellular metabolism. AHR signaling, which is required for epidermal γδ T cells to properly develop, becomes reduced during obesity [116,125]. In the absence of AHR, there are 50% fewer epidermal γδ T cells and the remaining γδ T cells express higher levels of inflammatory genes such as IFN-γ, granzyme F (GZMF), and programmed death-ligand 1 (PDL-1) [125].…”

“…AHR signaling, which is required for epidermal γδ T cells to properly develop, becomes reduced during obesity [116,125]. In the absence of AHR, there are 50% fewer epidermal γδ T cells and the remaining γδ T cells express higher levels of inflammatory genes such as IFN-γ, granzyme F (GZMF), and programmed death-ligand 1 (PDL-1) [125]. AHR signaling reduces inflammation and maintains homeostasis in the skin by inhibiting inflammatory genes and upregulating cell morphology and ion homeostasis genes [125].…”

“…In the absence of AHR, there are 50% fewer epidermal γδ T cells and the remaining γδ T cells express higher levels of inflammatory genes such as IFN-γ, granzyme F (GZMF), and programmed death-ligand 1 (PDL-1) [125]. AHR signaling reduces inflammation and maintains homeostasis in the skin by inhibiting inflammatory genes and upregulating cell morphology and ion homeostasis genes [125]. Upregulation of cell morphology F-actin enzymes Advillin and Fermt2 and ion homeostasis ion channels Kcnab and Kcnma1 allows for proper epidermal γδ T cell activation and downstream proliferation [125].…”

“…AHR signaling reduces inflammation and maintains homeostasis in the skin by inhibiting inflammatory genes and upregulating cell morphology and ion homeostasis genes [125]. Upregulation of cell morphology F-actin enzymes Advillin and Fermt2 and ion homeostasis ion channels Kcnab and Kcnma1 allows for proper epidermal γδ T cell activation and downstream proliferation [125]. Obesity reduces AHR signaling, causing fewer epidermal γδ T cells to round up and release cytokines upon activation, which leads to a delay in wound repair [116,125].…”

“…Upregulation of cell morphology F-actin enzymes Advillin and Fermt2 and ion homeostasis ion channels Kcnab and Kcnma1 allows for proper epidermal γδ T cell activation and downstream proliferation [125]. Obesity reduces AHR signaling, causing fewer epidermal γδ T cells to round up and release cytokines upon activation, which leads to a delay in wound repair [116,125]. Another mechanism of epidermal γδ T cell dysfunction in obesity and diabetes is the disruption of the IL-15-IGF-1 loop (Figure 2).…”